Purpose: To determine which competing macroscopic dose descriptor best tracks absorbed dose to biologically relevant subcellular targets via Monte Carlo analysis of cellular models for a variety of normal and cancerous tissues, and evaluate relations between bulk dose‐specification media and absorbed doses to cellular targets for kilovoltage radiation. Methods: The relative proportions of water, proteins, inorganic elements, and lipids in cell cytoplasm and nuclei, extracellular fluid, and the corresponding average bulk media were determined for normal and cancerous tissues through a literature review. Mass‐energy absorption coefficients, attenuation coefficients, and stopping powers for these media were calculated. Representative models of cells and cell clusters for normal and cancerous tissues were developed; doses to cellular targets were computed with Monte Carlo (MC) simulation for photon sources (energies between 20 keV and 380 keV) and compared to bulk medium dose descriptors. Results: Cells contain significant and varying mass fractions of proteins, inorganic elements, and lipids (adipocytes only). Variations in mass energy absorption coefficients for cytoplasmic and nuclear media as large as 10% compared to water are observed for sub‐50 keV photon energies (I‐125 and Pd‐103). In adipose tissues, 10% differences persist to 90 keV. Doses to cellular targets differ by up to 10% compared to doses to the corresponding average bulk medium or to water. The relationships between cellular target doses and doses to the bulk medium are sensitive to source energy and cell morphology, particularly for low energy brachytherapy. Conclusions: There are significant variations in cellular morphology (composition, size) with cell type; cells are not generally radiologically water equivalent. Thus neither dose to bulk medium nor dose to water in inhomogeneous macroscopic media quantitatively tracks energy imparted to biologically relevant subcellular targets for the range of cellular geometries investigated and kilovoltage photon sources.